1-methyl-delta-dehydroestrogens and process



Patented Mar. 2, 1954 1 PRO CESS

Carl Djerassi, George Rosenkranz, Stephen Kaufmann, John Pataki, andJesus Romo, Mexico City, Mexico,

assignors to Syntex S. A., Mexico City, Mexico, a corporation of MexicoNo Drawing. Application March 31, 1950, Serial No.

- 9 Claims. (Cl. 260-397.4)

The present invention relates to cyclopentanoper-hydrophenanthrenecompounds. More particularly the present invention relates to novelestrogens and the production thereof and especially l-methyl estrogens.

It has been previously set forth in the prior literature, as for exampleInhofien, Angew. Chem., vol. 59, p. 207, 1947, that the 1,4-diene-3-ones of the steroid series readily undergo aromatization of ring A witha concomitant migration of the angular methyl group to yield so-calledl-methyl phenols, as for example l-methyl estradiol, l-methyl estrone,etc. These compounds were insoluble in alkali and devoid of estrogenicactivity.

In accordance with the ous compounds have been prepared probablypossessing the l-methyl configuration and having very substantialestrogenic activity. Further, in

present invention varicompounds have clearly demonstrated theirdifference as by depression of the melting points.

"In application Serial No. 152,498, filed March 28,- 1950, a novelprocess for the production of novel A -3-ketosteroids. In particular,application Serial No. 152,498 discloses A -3-ketosteroids which may beexemplified by the following formula:

wherein A maybe 0:0 or CH-OR and R may be hydrogen, a lower alkyl group,as for example an aromatic anhydride or propionic acid anhydridetageth'err with paratoluene sulfonic acid will rearrange to thisapinvention that hours.

produce novel l-methyl-A -estrogens which exhibited estrogenicproperties.

It has been further discovered in accordancewith the present inventionthat the l-methyl A -estrogens thus produced could be readily'hydrogenated utilizing a hydrogenation catalyst to produce in goodyield l-methyl estrogens, as for example l-methyl estrone or l-methylestradiol, these novel l-methyl estrogens together with their ester andether derivatives exhibiting definite estrogenic properties and beingsoluble in dilute alkali.

It has further been found in accordance with the present invention thatthe l-methyl-A estrogens could be dehydrogenated in the pres-; ence of asuitable catalyst to produce the novel l-methyl equilenin andderivatives thereof.

The production of the novel l-methyl-A estrogen compounds of the presentinvention may be exemplified by the following equation: I CH3 I CH3 ICH: F

heat

o ssa es sulfonic acid l saponification CH: /D (13H: J

In the above equation A may represent the groups previously set forth.Rx represents the residue of acetic acid or in the event propionic'anhydride isused the residue of propionic acid. B represents C=O andCHORy and Ry may be a lower alkyl group, as for example methyl'or ethylor an aromatic group such as benzyl or the residue of a lower fatty acidor an aromatic acid as for example acetic acid, propionic acid orb'enzoic acid. D represents C=O or CHOH.

-In practicing the dienone phenol rearrangement above set forth amixture of trienone with paratoluene sulfonic acid and the acetic orpropionic anhy'dride could be heated on a steam bath for a'suitable Theresultant solution was then cooled period of time, as for example fiveand hydrolyzed by agitation with water and the crystalline product thusprecipitated was filtered, dried and recrystallized from a suitablesolvent, as for example an alcohol such as methanol. The products couldbe then further: recrystallized from similar organic solvents forpurification. The reaction proceeded both with the esters of the A-3-ketosteroids and also with the free compounds, i. e. those compoundswherein A is CH-OH, since those compounds were esterifie'd under theconditions of the reaction. For example the product of the dienonephenol rearrangement of A -androstatrien-Eld'l dione using aceticanhydride was 1-methyl-M-dehydroestrone acetate and the product of thedienone phenol rearrangement of both A -androstafiiensl l-ol- 3-one andits ll-acetate, was l-methyl-n -dehydroestradiol-3,l'l-diacetate. Theesters thus produced could then be converted to the free compounds as bysaponification with an alcoholic solution of a suitable alkali metalhydroxide by refluxing the ester therewith. Sulfonic acid: could be alsoused as a catalyst in. place of the toluene sulfonic acid for therearrangement of the alcohols and derivative compounds, i. e. where Awas CH-OR, and in this casethe reaction was carried out at roomtemperature.

The lmethyl-A -dehydro'estrone compounds may also he reduced utilizinglithium aluminum hydride to the corresponding l-methyl-nd'ehydroestradiol compounds. This reaction may be performed generally bydissolving the l-methyl-M-dehydroestrone acetate for: example in a drysolvent, i. e. preferably an ether solvent, and refluxing the same withlithium aluminum hydride. The Imethyl-M-dehydroestradiol which is thusproduced is entirely similar to that produced by the dienone phenolrearrangement previously set forth.

The l-methyl-A compounds produced in accordance with the foregoingreaction can be readily hydrogenated to the corresponding 1- methylestrogen in accordance with the following equation:

catalytic F 3,0 hydrogenation saponlflcation acetate could then besaponified to produce 1- methyl estrone.

The 1-methyl-A -dehydroestrogens can also be dehydrogenated to producethe corresponding novel. r-methyl equilenin compounds in accordancewiththe following reaction:

dehydrogenation selenium dioxide In the above reactions Rx, B and Drepresent the same groups as previously set. forth.

In the above reaction the preferred dehydrogenating agent is selenium:dioxide. However, other common dehydrogenating agents, such aspalladized charcoal, other precious metal catalysts, chloranil and thelike may be used. In general the 1-methyl-A -dehydroestrogen isdissolved in a suitable solvent such as acetic acid or dioxane andrefluxed for a. short period of time with the catalyst under anatmosphere of nitrogen. The reaction mixture is then filtered to removethe selenium and the filtrate diluted with water. The resultant productis then filtered and recrystallyzed from a suitable solvent, such asmethanol. The esters produced may then be saponified as previously setforth.

The following specific examples serve to illustrate the presentinvention but are not intended to limit the same:

Example I A mixture of 1-5.5 g. or A -androstatrien- 3 ,l'7-dione, 3.90g. oi p-toluenesulfonic acid and 600 cc. of acetic anhydride was heatedfor five hours on av steambath. The cooled solution was hydrolyzed byswirling with water, the crystaline product was filtered, dried andrecrystallizedfrom methanol; yield, 12.85 g. (72%), melting pointI47-149 C. Further recrystallization from the same solvent gave purel-methyl-n -dehydroestrone acetate with a melting point of 152-153 C. Mi-94 (dioxane); ultra-violet maxima at 222 mu (log E 4.44) and 264 mu(log E 3.93).

Analysis: Calculated for Carl-124032 H, 7.46. Found: C, 78.09; H, 7.53.

Example II Saponification of the acetate of Example I was accomplishedin 97% yield by refluxing with 2% methanolic sodium hydroxide solutionfor one hour. Two recrystallizations from methanol gave 1-methyI-A-dehydroestrone with a melting point of 250-252 C. [al -87.7(chloroform), -l6.3 (dioxane); ultra-violet maxima at 228 mu (log E4.49), 268 mu (log E 3.90) and 306 mu (log E 3.28).

Example III A mixture or 2.7 g. of A -androstatrien-N ol-3-onel'T-acetate, 100 cc. of acetic anhydride and 1 g. of p-to'luene sulfonicacid was subjected to the same procedure as in Example I. 2.89; g.-(95%) of 1-methyl-A -dehydroestradiol 3,l7-di, acetate was produced witha melting point of 110-113 C. Recrystallization from hexane gave in 71%yield the purified compound with a melting point of 116-117 C. [a] 49;ultra-violet maxima at 222 mu (log E 4.46) and 264 mu (log E 3.96).

Analysis. Calculated for (323112804: C, 74.97, H, 7.65. Found: C, 74.76,H, 7.38.

This same rearrangement was also efiected utilizing the free 17 hydroxycompound which was acetylated under the conditions of the rearrangementto produce the, same product. The same reaction was also carried oututilizing 10% by weight of sulfuric, acid as the catalyst instead of thep-toluene sulfonic acid. When sulfuric acid was used as the catalyst,the reaction was preferably carried out at room temperature.

Example IV I Saponification of the diacetate of Example III by refluxingwith 2% methanolic sodium hydroxide solution similarly to Example IIproduced in substantially quantitative yield 1-methyl-A-dehydroestradiol having a melting point of 130-132 C. This meltingpoint was unchanged after several recrystallizations from either hexaneacetone or dilute methanol, [a] 124 (chloroform), -134 dioxane;ultra-violet maxima at 226 mu (log E 4.57) and 266 mu (log E 3.95).

Analysis. Calculated for C19H24O2! C, 80.24, H, 8.50. Found: C, 80.48,H, 8.50.

The phenol produced was readily soluble in 2N aqueous sodium hydroxideand was benzoylated by the Schotten-Baumann method to produce 1-methyl-n-dehydroestradiol 3-monobenzoate having a melting point of 146- 47.5 C.after recrystallization from hexane-acetone, [e] --l28.

Analysis. Calculated for 0261-12803: C, 80.42, H, 7.27. Found: C, 80.35,H, 7.19.

Example V A solution of 2 g. of 1-methyl-A -dehydroestrone acetate ofExample I in 600 cc. of dry ether was refluxed with 1 g. of lithiumaluminum hy-' dride for thirty minutes. After the usual workup, therewas obtained 1.54 g. (88%) of l-methyl- M-dehydroestradiol having amelting point of 129-132 C., which gave no depression on admixture withthe sample prepared according to Example IV and possessed the samerotation and spectrum.

Example VI A solution of 4 g. of 1-methyl-A -dehydroestrone acetatehaving a melting point of 147-149 C. of Example I in 60 cc. of ethylacetate was shaken in the presence of hydrogen with 800 mg. of 10%palladium-on-charcoal catalyst for two hours, at which the time hydrogenup-take corresponded to one mol. After filtration, evaporation andrecrystallization from methanol, 3.5 g. (87%) of l-methylestrone acetatewas obtained having a melting point of 157.5-158.5 C. [a] l--224(chloroform),+219 (dioxane); ultra-violet maximum at 268 mu (log E 2.52)and maximum at 252 mu (log E 2.31). It is to be noted that the so-calledl-methylestrone described in the literature did not form a crystallineacetate.

Analysis. Calculated for C21H26O32 C, 77.26; H, 8.02. Found: C, 77.14;H, 8.20.

Example VII Alkaline saponificaticn of the l-methylestrone acetate ofExample VI in accordance with the proximately one-half the estrogenicpotency of estrone in rats.

Analysis. Calculated for C19H24O2I H, 8.50. Found: C, 80.05; I-I, 850.

Example VIII Hydrogenation of the A -dehydro diacetate of Example III inthe manner described in Example VI, in ethyl acetate solution with 10%palla-' dium-on-charcoal catalyst (barium sulfate sup ported catalystwas equally satisfactory) afforded 81% of shiny, prismatic blades (frommethanol) of l-methylestradiol-3,l'l-diacetate with a melting point of178- C. [a] +'111; ultra-violet maximum at 268 mu (log E 2.53) andminimum at 252 mu (log E 2.44). The so-called l-methylestradiol3,17-diacetate described in the literature had a melting point of138.5-139.

Example IX l-methylestradiol, prepared either by saponification of itsdiacetate of Example VIII or by hydrogenation of 1methyl-A-dehydroestradiol of Example IV in accordance with the procedure ofExample VI, was obtained from ether-hexane as a microcrystalline powder,which shrank at C. and melted at 1l0-1l6 C. [al +146; ultra-violetmaximum at 284 mu (log E 3.28) and minimum at 250 mu (log E 2.25). Thephysical constants of this alkali-soluble estrogenically potent phenolare. in complete contrast to those reported for the so-calledl-methylestradiol: insoluble in alkali, crystallizes readily, meltingpoint 235.5-2365" [a] +135 (dioxane).

Analysis. Calculated for C19H26O21 C, 79.67; H, 9.14. Found: 0.79.87; H,9.36.

Example X Example XI A solution of 1 g. of l-methyhM-dehydrOestroneacetate of Example I in 20 cc. of glacial acetic acid or dioxane wasrefluxed for ten minutes with 0.17 g. of freshly sublimed seleniumdioxide under nitrogen. After filtration of selenium, the solution wasdiluted with water, the pink solid (0.90 g., melting point -165 C.) wasfiltered and recrystallized from methanol, yielding 0.62 g. ofl-methylequilenin acetate as colorless crystals with a melting point ofI'll-172.5 C. [a] =+113.

Analysis. Calculated for CzrHzzOc: C. 78.23; H, 6.88. Found: C, 78.54;H, 6.98.

a melting point of 250-252" 0..

Example XIII A mixture of 1 g. of l-methyl-A -dehydroestradiol3,1'7-diacetate, 0.15 g. of selenium dioxide and cc. of glacial aceticacid was refluxed for fifteen minutes. After filtering, pouring intowater and recrystallizing from hexane-acetone, colorless plates ofl-methyl-1'7-dihydroequilenin 3,17-diacetate with a melting point of136-137" C. [a] 15 (chloroform) was obtained. Saponification andrecrystallization from aqueous methanol or hexane-acetone yieldedl-methyl-l'T-dihydroequilenin-l'lfl, having a melting point of 225-227C. [a] +33 (dioxane).

The last-mentioned compound could also be obtained by lithium aluminumhydride reduction of the l-methyl equilenin acetate of Example XI.

We claim:

1. A process for the production of l methyl-o estrogen compounds havingthe following formula:

3 CH: t

wherein RX is selected from the group consisting of the residue ofacetic acid and the residue of propionic acid, B is selected from thegroup consisting of C=O, CI-I-O acyl of a lower fatty acid and CH-Obenzoate, comprising heating a compound of the following formula:

(PH: OH: fl

wherein A is selected from the group consisting of C=O. CH-OH, CH-O acylof a lower fatty acid and GIL-O benzoate, with an acid anhydride 8p-toluene sulfonicf acid to produce the ester of l-methyl A-dehydroestrone and thereafter saponifying said ester.

3. A process for producing I-methyl-A -dehydroestradiol, comprisingheating a compound selected from the group consisting of A-androstatrien-l7-ol-3-one and esters of A -androstatrien-l'7-ol-3-onewith an acid anhydride selected from the group consisting of aceticanhydride and propionic anhydride together with ptoluene sulfonic acidto produce the ester of 1- methyl-M-dehydroestradiol and thereaftersaponifying said ester.

4. A process for producing l-methyl-n -dehydroestradiol, comprisingreacting a compound A -anselected from the group consisting ofdrostratrien-l'T-ol-B-one and esters of A -androstatrien-17-ol-3-onewith an acid anhydride selected from the group consisting of aceticanhydride and propionic anhydride together with sulfuric acid to producethe ester of l-methylnf -dehydroestradiol and thereafter saponifyingsaid ester.

5. A 1-methyl-M-dehydroestrogen compound I having the following formula:

wherein R2 is selected from the group consisting of hydrogen, theresidue of acetic acid and the residue of propionic acid and A isselected from the group consisting of Ca -O, CHOH, CH-O ac'yl of a lowerfatty acid and CH-O benzoate.

6. A new compound, comprising l-methyl-n dehydroestrone acetate having amelting point of 152-153 C.

7. A new compound, comprising l-methyl-n dehydroestrone having a.melting point of 250- 253 C.

8. A new compound, comprising l-methyl-M-dehydroestradiol-3,17-diacetate having a melting point of 1164.17 C.

9. A new compound comprising l-methyl-n dehydroestradiol having amelting point of 132 C.

CARL DJERASSI. GEORGE ROSENKRANZ. STEPHEN KAUFMANN. JOHN PATAKI.

JESI'IS ROMO.

Name Date Inhofien Apr. 28, 1942 Number

1. A PROCESS FOR THE PRODUCTION OF 1-METHYL-$6ESTROGEN COMPOUNDS HAVING THE FOLLOWING FORMULA: 